The enclosed proposal outlines the dynamic training and systematic research plans for Dr. Gene Webb for K01 funding. Dr. Webb plans an integrated and intensive training program in the area of beta-cell signal transduction and its impact on stimulation of insulin synthesis. The proposed work and unique training environment at The University of Chicago will allow Dr. Webb to achieve his long-term goal of a fully independent research career in the field of diabetes. Training and development will entail intensive mentoring by Dr. Fredric Wondisford and Dr. Donald Steiner, including weekly meetings, review of manuscripts and grants, as well as a biannual meeting by an advisory committee to chart progress and provide oversight. Additionally, course work, campus seminars and attendance at national meetings are integral components of Dr. Webb's program. Further, Dr. Webb's participation in The University of Chicago's NIH Diabetes Research and Training Center (DRTC) will augment both his research and career development. The research component of the proposal tests the hypothesis that metabolic stimulation of beta cells induces specific signal-transduction pathways that differentially regulate the translation of proinsulin. These mechanisms may contribute to the development of type 2 diabetes. In Specific Aim 1, a systematic research plan will be undertaken to define signal transduction components that are glucose-stimulated in beta cells and that also impact the ability of the cell to produce insulin. This will include signaling through the mTOR pathway, activation of the p38 MAP kinase pathway, and insulin signaling on the beta cell. Because each pathway regulates multiple downstream kinases, these will be investigated also. The impact on proinsulin synthesis will be compared to tubulin synthesis for each pathway to determine effects specific to proinsulin synthesis. In Specific Aim 2, the functional consequence of signaling through these pathways on protein translation factors in the beta cell is studied. This will look first at translation initiation, a step previously shown to be crucial in proinsulin translation. Again, effects specific to proinsulin will be determined. Specific Aim 3 utilizes microarray techniques to identify and characterize glucose-responsive signal transduction components in the beta cell to gain a comprehensive view of metabolic signaling.